JPH05192094A - Granulated composition - Google Patents

Abstract

PURPOSE:To stabilize a lankacidin antibiotic substance in a feed by agglomerating a lankacidin antibiotic substance with a low-melting adjuvant and adding the obtained granulated composition to a feed. CONSTITUTION:The objective granulated composition is produced by agglomerating a lankacidin antibiotic substance with a low-melting adjuvant having a melting point of >=40 deg.C. The granulated composition can be obtained by stirring the lankacidin antibiotic substance and the low-melting adjuvant having a melting point of >=40 deg.C under heating at a temperature above the melting point of the adjuvant and cooling the obtained granules to a temperature below the melting point.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a granulation composition and a method for producing the same. More specifically, the present invention relates to a granulation composition capable of stabilizing a Lancacidin antibiotic that is easily decomposed in feed, particularly a feed additive.

[0002]

2. Description of the Related Art In livestock farming, a method of mixing a drug with a feed and administering it for the purpose of preventing or treating diseases such as pigs and chickens or reinforcing nutritional components is widely used. But,
Generally, the proportion of antibacterial agents and vitamins in feed is several pp
Since it is low from m to several hundred ppm, and has a high water content of 13 to 15% in the feed, and also contains a highly hygroscopic component such as choline chloride, the catalytic action of minerals in the feed and the rancidity of fats and oils. It is the actual situation that it is susceptible to decomposition such as oxidation or hydrolysis due to the above.

[0003]

Among the above drugs, among others,
Lancacidin compounds are unstable in feed, and there is a strong demand for the development of stable formulations.

[0004]

Means for Solving the Problems The inventors of the present invention have made extensive studies in view of the above-mentioned circumstances, and as a result, as a result, a lancacidin antibiotic was used alone or as a binder together with a disintegrant, a surfactant, a stabilizer and a granulation nucleus. Fusing with a low melting point adjuvant used as, that is, without forming a continuous phase of the adjuvant, the granulation composition obtained by simultaneously incorporating each component into the unit particles together with the adjuvant, feed It was found that there is a remarkable effect on the stabilization in the above, and further research was conducted to complete the present invention. That is, the present invention provides (1) Lancacidin antibiotics having a melting point of 40 ° C.
A granulation composition obtained by fusion bonding with the above low melting point adjuvant, (2) a feed additive containing the granulation composition according to (1) above, (3) a lancacidin antibiotic and a melting point of 40 ° C or higher. The present invention relates to a method for producing a granulated composition according to the above (1), which comprises stirring and granulating a low melting point adjuvant while heating it at a temperature equal to or higher than the melting point of the adjuvant, and then cooling to a temperature equal to or lower than the melting point.

In the present invention, the Lancacidin antibiotics include, for example, Streptomyces rotiei bar borbilis [this strain is Micro Engineering Research Institute (FRI), Fermentation Research Institute (IFO), American Type Culture Collection]. (ATCC) to FERM P-61 respectively
55, IFO-12507, ATCC-21250], etc., which are antibiotics that are produced and accumulated by culturing Streptomyces spp., Such as Lankacidines, derivatives thereof and salts thereof [JP-A-62-62]. 240687 gazette]. As the lancacidins, those having a structure represented by the following general formula are known.

[Chemical 1] In the above general formula, the compound of Ra = COCH ₃ is Lancassidin A (hereinafter sometimes referred to as sedecamycin)
The compound of a = H represents Lancacidin C. Lancacidin C is obtained by culturing the above-mentioned Streptomyces genus microorganism [Japanese Patent Publication No. 47-20959]. Lancacidin A is the same as Lancacidin C in Japanese Patent Publication No. 48-7.
It can be produced by acylation by the method described in Japanese Patent Publication No. 4). Examples of derivatives of lancasidins include, for example, 8th position and / or 14th of lancassidine C.
Ester form [chemistry and biology, Volume 15, 337-3
42 (1977); Takeda Research Institute (Journal of the T
akeda Research Laboratories), Volume 41, 81-
113 (1982)], 8th and / or 14th
Derivatives of Acyloxy etc. [The Journal of
Antibiotics (The Journal of Antibiotics)
26, p. 647 (1973)], 8-substituted alkyl esters, carbonic acid esters and substituted carbamate derivatives [JP-A-62-240687] are known. Lancacidin A carbamate is produced by the reaction of Lancacidin A with isocyanates and the reaction of Lancacidin A with pentachlorophenoxy or 2,4,5-trichlorophenoxy carbonates and amines in JP-A-62-240687. Is listed. A method for producing a lancasidin A carbamate derivative is described in JP-A-3-130290. Mepicedemycin used in Examples 2 and 3 described later was prepared by the method described in these publications.
Can be manufactured more.

The Lancacidin antibiotics used in the present invention may be those having a melting point of higher than 40 ° C., but those having a melting point of 100 ° C. or higher are preferably used. For example, they have a structure represented by the following general formula. There are things.

[Chemical 2] Z represents an oxygen atom or a sulfur atom, and R ⁵ represents an organic residue via a carbon atom. ) Group or (i
i) R ¹ and R ² together form the formula

[Chemical 3] (In the formula, R ⁶ represents acyl, sulfonyl or alkoxycarbonyl, and R ⁷ represents lower alkyl.). R ³ and R ⁴ are the same or different and each represents a hydroxy, halogen, azide or an organic residue through an oxygen atom, a sulfur atom or a nitrogen atom. Provided that R ¹ is a hydrogen atom and R ² is

[Chemical 4] Indicates alkyl. ) Is a group represented by
³ is hydroxy or the formula -OCOR ⁹ (wherein R ⁹ is alkyl, alkenyl, aralkyl, aryl, 3-pyridyl, -CF ₃ , m-bromophenyl or -CH ₂ CH ₂
Indicates COOH. ) And R ⁴ is not hydroxy or the formula —OCOR ^{9 where} R ⁹ is as defined above, or R ³ and R ⁴ are not both formyloxy,
¹ is a hydrogen atom, R ² is —COCOCH ₃ and R ⁴ is —OC.
When OCH ₃ , R ³ is chlorine,

[Chemical 5] Where R ² is —COCOCH ₃ and R ³ is —OCH ₃ , then R ⁴ is not —OCH ₃ . ] The compound or its salt represented by these.

As an example of these, decedamicin (R ₁ = H, R ₂ = COCOCH ₃ , R ₃ = OH, R ₄ = O
COCH ₃ ), Lancacidin C (R ₁ = H, R ₂ = COC
OCH ₃ , R ₃ = OH, R ₄ = OH), Lancacidin D
(R ₁ = H, R ₂ = COCHOHCH ₃ , R ₃ = OH, R ₄
= OCOCH ₃ ), Lancacidin F (R ₁ = H, R ₂ = C
OCHOHCH ₃ , R ₃ = OH, R ₄ = OH), mepicedomycin (R ₁ = H, R ₂ =

[Chemical 6] AMA-2195 (R ₁ = H, R ₂ = COCOCH ₃ , R
₃ = OCOSCH ₂ CH ₂ N (CH ₃ ) ₂ , R ₄ = OCOC
H ₃ ), AMA-2195F (R ₁ = H, R ₂ = COCH
OHCH ₃ , R ₃ = OCOSCH ₂ CH ₂ N (CH ₃ ) ₂ , R _{4
= OCOCH 3), AMA-2196} (R 1 = H, R 2 =
COCOCH ₃ , R ₃ = OCOSCH ₂ CH ₂ N (CH ₃ ) ₂ ,
_{R 4 = OH), AMA-} 2196F (R 1 = H, R 2 = C
OCHOHCH ₃ , R ₃ = OCOSCH ₂ CH ₂ N (C
_{H 3) 2, R 4 =} OH), AMA-2309 (R 1 = H, R 2
= COCOCH ₃ , R ₃ = OCOCH ₂ N (C ₂ H ₅ ) ₂ , R ₄
= OCOCH ₃ ), A MA-2309F (R ₁ = H, R ₂
= COCHOHCH ₃ , R ₃ = OCOCH ₂ N (C ₂ H ₅ ) ₂ ,
R ₄ = OCOCH ₃ ), AMA-2310 (R ₁ = H, R ₂
= COCOCH ₃ , R ₃ = OCOCH ₂ N (C ₂ H ₅ ) ₂ , R ₄
= OH), AMA-2310F (R ₁ = H, R ₂ = COC
_{HOHCH 3, R 3 = OCOCH 2} N (C 2 H 5) 2, R 4 = O
H) and those having a basic group include salts thereof (hydrochloride, sulfate, nitrate, tartrate, etc.).

[0008] Lancacidin antibiotics are used as powder or particulate powder, and the average particle diameter thereof is preferably 0.1 µm to 5 mm, preferably 10 µm to 0.5 mm. The amount of the lancacidin antibiotic is usually about 1 to 90% of the granulation composition, preferably about 10 to 70%.
%, The stability of the Lancacidin antibiotics used,
It can be appropriately changed depending on the physical properties of the powder. Examples of the adjuvant include water-soluble adjuvants represented by polyethylene glycol, polypropylene glycol, polyoxyethylene polypropylene copolymer, polyethylene ester, polyethylene sorbitan ester, etc. and hydrogenated beef tallow, hydrogenated soybean oil, hydrogenated rapeseed oil, hydrogenated castor oil, hydrogenated Palm oil, hydrogenated cottonseed oil, hydrogenated whale oil, hydrogenated fish oil, cacao butter, lard, beef tallow, glycerin distearate, glycerin monostearate, and other beeswax, beeswax,
Fat-soluble adjuvants such as carnauba wax, spermaceti wax, and higher fatty acids such as palmitic acid, stearic acid, and behenic acid can be mentioned. However, since the lancacidin antibiotics are unstable to water, they are used as feed. When mixed and stored therein, a fat-soluble adjuvant is preferably used. The adjuvant preferably has a melting point of 40 ° C. or higher and has a low melting point region, and further has a low melting point of 100 ° C. or lower, especially 40 ° C. to 90 ° C., especially 50 ° C.
~ 70 ° C is preferred. These adjuvants may be used alone or in combination of two or more. The adjuvant may be in any form such as powder, granules, flakes, and heat-melted liquid. The amount of the adjuvant to be added may be in a range such that the adjuvant can form the particles by combining the components in the composition without forming a continuous phase.
Therefore, although it is appropriately changed depending on the physical properties (eg, particle size, etc.) of the Lancacidin antibiotic and other components in the granulation composition, it is usually about 1 to 40%, preferably about 5% of the granulation composition. It is selected within the range of 20%.

The granulating composition of the present invention contains a disintegrating agent, a surfactant, a stabilizer, a granulating nucleus, a bulking agent, a coloring agent, a flavoring agent, etc., in addition to the above-mentioned Lancacidin antibiotics and adjuvants. You may add as needed. The granulated composition of the present invention is preferably a powder or fine granules from the viewpoint of mixability upon addition of feed etc., for example, No. 16 (opening 1
000 μm) particles that pass through 90% or more of a sieve, particularly particles that pass through No. 20 (opening 840 μm) sieve of 90% or more, and the smaller the particle size, the more preferable. However, granulation improves the fluidity and simplifies handling, and suppresses the inhalation of drug dust to ensure the safety of the user. Therefore, the average particle size is about 50-500μ.
m, and particularly preferably 100 to 300 μm. The granulation composition of the present invention is used for the prevention and treatment of microbial infections (for example, monogastric livestock such as pigs and horses, poultry such as chickens, ducks and ducks, and other pets such as dogs and cats). It may be administered alone to animals, etc., and may be used by adding it to feed as an additive together with other components such as vitamins, minerals, plant meal, etc. In particular, porcine dysentery, mycoplasma disease of pigs and chickens Useful for prevention and treatment.

[0010]

EXAMPLES The present invention will be described in more detail below with reference to Examples and Experimental Examples, but the present invention is not limited thereto. Example 1 Cedecamycin 50.0 g, carboxymethyl cellulose calcium (Nichirin Kagaku) 50.0 g, sucrose fatty acid ester (Daiichi Kogyo Seiyaku Co., Ltd.) 40.0 g, butylhydroxyanisole (Orient Chemical) 0.5 g, dibutylhydroxytoluene (Takeda Foods) ) 0.5 g, rice bran oil cake (Tsukino food) 279.0 g and stearic acid (Nippon Yushi) 130.0 g were put in a 6-liter super mixer (Kawata Manufacturing Co., Ltd.) and stirred at about 85 ° C. and 1000 rpm for 10 minutes. Mix with a 5 liter V-type mixer (Tokuju Kosakusho) at 500 rpm for 10 minutes at room temperature, cool, and sieve through a No. 20 sieve (840 μm) to obtain a particle size of 84.
939.7 g of a granulated composition of sedeccamycin having a particle size of 0 μm or less (average particle size 150 μm) was prepared.

Example 2 Mepicedemycin 160.0 g, carboxymethylcellulose calcium (Nichirin Kagaku) 16.0 g, sucrose fatty acid ester (Daiichi Kogyo Seiyaku Co., Ltd.) 12.8 g, butylhydroxyanisole (Orient Chemical) 0.16
g, Butylhydroxytoluene (Takeda Foods) 0.16
g, defatted rice bran (Tsukino food) 102.08g and stearic acid (Nippon Yushi) 28.8g were put in a 2 liter high speed mixer (Fukae Kogyo), about 90 ° C, 1000
After stirring at rpm for 4 minutes, mix gently in a plastic bag, cool at room temperature for about 5 minutes, and sieve through a No. 30 sieve (500 μm) to obtain a granulated composition of mepicedemycin having a particle size of 500 μm or less (average particle size 190 μm). 307.2 g of the product was produced.

Example 3 Mepicedemycin 350.0 g, carboxymethyl cellulose calcium (Nichirin Chemical) 35.0 g, sucrose fatty acid ester (Daiichi Kogyo Seiyaku Co., Ltd.) 28.0 g, butylhydroxyanisole (Orient Chemical) 0.35.
g, dibutylhydroxytoluene (Takeda Foods) 0.35
g, 223.3 g of defatted rice bran (Tsukino food) and 63.0 g of stearic acid (NOF Corporation) were put into a 2 liter high speed mixer (Fukae Kogyo), and the temperature was about 85 ° C and 1000 rp.
After stirring at m for 3 minutes, mix lightly in a plastic bag, cool at room temperature for about 5 minutes, and sieve through a No. 20 sieve to obtain a particle size of 840.
665.4 g of a granulation composition of mepicedemycin having an average particle diameter of 210 μm or less was prepared.

Example 4 150.00 g of cedecamycin, 15.00 g of carboxymethyl cellulose calcium (Nichirin Kagaku), 12.00 g of sucrose fatty acid ester (Daiichi Kogyo Seiyaku), butylhydroxyanisole (Orient Chemical) 0.1
5 g, dibutylhydroxytoluene (Takeda Foods) 0.1
5 g and defatted rice bran (Tsukino food) 83.70 g were put into a 2 liter high speed mixer (Fukae Kogyo) and mixed at about 85 ° C. and 200 rpm for 10 minutes, and then melted stearic acid (NOF) 39.00 g Add 5 more
After stirring at 00 rpm for 10 minutes, mix gently in a plastic bag, cool at room temperature for about 5 minutes, and then sieve No. 18 (850μ
m) and the particle size is 850 μm or less (average particle size 15
54.6 μm) of a granulated composition of cedecamycin, 264.6 g.

Example 5 Mepicedemycin 150.00 g, carboxymethyl cellulose calcium (Nichirin Kagaku) 15.00 g, sucrose fatty acid ester (Daiichi Kogyo Seiyaku Co., Ltd.) 12.00 g, butyl hydroxyanisole (Orient Chemical) 0.001 g.
15g, dibutylhydroxytoluene (Takeda Foods) 0.1
5g and 89.70g of defatted rice bran (Tsukino food) were put into a 2 liter high speed mixer (Fukae Kogyo) and about 8
After mixing at 5 ° C and 200 rpm for 10 minutes, 33.00 g of melted stearic acid (NOF Corporation) was added and the mixture was further added to 50
After stirring at 0 rpm for 10 minutes, mix gently in a plastic bag, cool for about 5 minutes, and filter through a No. 18 sieve (850 μm) to obtain a granulated composition 270 of mepicedemycin having a particle size of 850 μm or less (average particle size 170 μm). 0.0 g was produced.

Example 6 150.00 g of acetylmepicedemycin hydrochloride, carboxymethyl cellulose calcium (Nichirin Chemical) 1
5.00 g, sucrose fatty acid ester (Daiichi Kogyo Seiyaku) 1
2.00 g, butylhydroxyanisole (Orient Chemical) 0.15 g, dibutylhydroxytoluene (Takeda Foods) 0.15 g and defatted rice bran (Tsukino Foods) 6
5.70 g was put into a 2 liter high speed mixer (Fukae Kogyo) and mixed at about 85 ° C. and 200 rpm for 10 minutes, and then melted stearic acid (NOF) 57.00 g
After adding and stirring at 500 rpm for 10 minutes,
Granule composition 272. Acetylmepicedemycin hydrochloride with a particle size of 850 μm or less (average particle size 200 μm) by gently mixing in a plastic bag, cooling for about 5 minutes at room temperature, and sieving with a No. 18 sieve (850 μm). 1 g was made.

Experimental Example 1 10 ppm of the granulation composition obtained in Example 1 was added to a piglet feed.
(10 mg / kg) was mixed, put in a kraft paper bag and stored at room temperature for 2 months, and then the content of decedamicin was measured by liquid chromatography.

[Table 1] Stability of granulated composition in feed ^a (ppm) ──────────────────────────────── At the beginning Room temperature 1 month Room temperature 2 months ─────────────────────────────── The granulation composition of Example 1 9.76 (100 ) ^c 9.98 (102) 9.44 (97) Reference ^b 9.61 (100) 9.37 (98) 8.74 (91) ───────────────────────── ────── a. Piglet feed (Japanese blended feed) b. Untreated drug substance of cedecamycin used in Example 1 c. () Indicates the residual rate (%) when the starting point is 100.

Experimental Example 2 The granulation composition obtained in Example 1 was added to a piglet feed at 10 ppm.
After compounding, it is molded into pellets and put in an aluminum bag for 25
After storing at 4 ° C. for 4 weeks, the content of decedamicin was measured by liquid chromatography.

[Table 2] Stability of granulated composition in pellet ^a (ppm) ────────────────────────────── Sample feed ^a Medium Pellet ───── ───────────────── At the start Immediately after production 25 ℃, 2 weeks 25 ℃, 4 weeks ──────── ─────────────────────── Granulation composition of Example 1 9.81 (100) ^c 7.24 (74) 6.11 (62) 6.12 (62) Reference ^b 9.00 (100) 4.77 (53) 3.61 (40) 3.09 (34) ────────────────────────────── a Feed for piglets (Japanese mixed feed) b. Unprocessed raw material of sedeccamycin used in Example 1 c. () Indicates the residual rate (%) when the starting point in the feed is 100.

Experimental Example 3 The granulation composition obtained in Example 2 was added to a piglet feed at 10 ppm.
After mixing, put in an aluminum bag and store at 40 ℃ for 8 weeks,
The content of mepicedemycin was measured by liquid chromatography.

[Table 3] Stability of granulated composition in feed ^a (ppm) ─────────────────────────────── Start 40 ° C, 2 weeks 40 ° C, 4 weeks 40 °, 8 weeks ─────────────────────────────── Granulation composition of Example 2 9.31 (100) ^c 9.01 (97) 8.62 (93) 8.50 (91) Reference ^b 7.10 (100) 4.27 (60) 3.64 (51) 2.66 (37) ──────── ──────────────────────── a. Piglet feed (Japanese blended feed) b. Mepicedemycin untreated drug substance used in Example 2 c . () Indicates the residual rate (%) when the start time is 100

Experimental Example 4 100 pp of the granulation composition obtained in Example 3 was added to feed for piglets.
m, 200ppm for broiler feed, 200 for adult chicken feed
After being blended with ppm, placed in an aluminum bag and stored at 30 ° C. for 4 weeks, the mepicedemycin content was measured by liquid chromatography.

[Table 4] Stability of granulated composition ^a in feed (ppm) ─────────────────────────────── Start 30 ℃, 2 weeks 30 ℃, 4 weeks ────────────────────────────── Piglets 90.4 (100) ^b 92.0 (102) 94.7 (105) For broiler 194.7 (100) 192.6 (99) 196.5 (101) For adult chicken 191.8 (100) 190.7 (99) 186.8 (97) ────────────── ───────────────── a. Mepicedemycin granulation composition obtained in Example 3 b. In parentheses, the residual rate (%) when the start time is 100 )

Experimental Example 5 100 ppm (100 mg) of the granulated composition obtained in Experimental Examples 4, 5 and 6 was added to a piglet feed (Japanese compound feed), respectively.
100 g of the mixed feed was placed in a glass bottle (closed stopper) and stored at 40 ° C. for 2 weeks. Then, the contents of sedecamicin, mepicedecamicin and acetylmepicedecamicin hydrochloride were measured by liquid chromatography.

[Table 5] Stability of granulated composition in feed ^a (ppm) ────────────────────────────────── Feeding start 40 ℃, 2 hours ────────────────────────────────── Granulation composition of Example 4 Product 96.4 (100) ^e 89.0 (92.3) Untreated raw material of Example 4 ^b 97.7 (100) 79.0 (80.9) Granulation composition of Example 5 91.6 (100) 86.3 (94.2) Untreated drug substance ^c of Example 5 ^c 90.0 (100) 69.6 (77.3) Granulation composition of Example 6 90.0 (100) 82. 8 (92.0) Untreated drug substance of Example 6 ^d 93.8 (100) 58.3 (62.2) ────────────────────── ──────────── a. Feed for piglets (Japanese blended feed) b. Sedecamycin drug substance used in Example 4 c. Mepicedecamycin drug substance used in Example 5 d. Acetylmepicedecamycin hydrochloride drug substance used in Example 6 e. () Indicates the remaining rate (%) when the start time is 100

[0021]

INDUSTRIAL APPLICABILITY In the granulation composition of the present invention, the active ingredient lancasidin antibiotic is fused with an adjuvant, that is, the molten adjuvant forms a discontinuous phase without forming a continuous phase. While granulating Lancacidin antibiotics, it is possible to stabilize the unstable Lancacidin antibiotics in the feed without reducing the activity of the Lancacidin antibiotics when administered to animals,
It is also highly useful as a feed additive. The method for producing the granulated composition of the present invention is a method of granulating without using an organic solvent, water, etc., simply by changing the temperature of heating and cooling, and it is simple and safe without the need for drying. It is an inexpensive and expensive manufacturing method. Further, since the Lancacidin antibiotics are rapidly decomposed when they come into contact with water, hydrolysis granulation cannot be performed, but according to the present melt granulation method, granulation can be performed without being decomposed at all.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI technical display location A61K 47/34 B 7433-4C J 7433-4C 47/44 B 7433-4C J 7433-4C

Claims (5)

[Claims] 1. A granulation composition comprising a lancacidin antibiotic fused with a low melting point adjuvant having a melting point of 40 ° C. or higher. 2. A feed additive containing the granulation composition according to claim 1. 3. The feed additive according to claim 2, which is added to chicken feed. 4. The feed additive according to claim 2, which is added to pig feed. 5. Lancacidin antibiotic and melting point 40 ° C.
The method for producing a granulated composition according to claim 1, wherein the low melting point adjuvant is stirred and granulated while being heated at a temperature equal to or higher than the melting point of the adjuvant, and then cooled to a temperature equal to or lower than the melting point.